FAPI PET in musculoskeletal oncology: An update and future directions

Fibroblast activation protein inhibitor (FAPI) imaging has become a promising approach in musculoskeletal oncology, with growing evidence supporting its application in both primary sarcomas and skeletal metastatic disease. Fibroblast activation protein (FAP) is expressed by cancer-associated fibroblasts and by tumor cells themselves in several sarcoma subtypes, while demonstrating limited expression in normal adult tissues. This biological profile has supported the development of radiolabeled FAP inhibitors, which provide high tumor-to-background contrast on PET imaging and enable theranostic applications with FAP-targeting radioligands. In sarcoma, available studies demonstrate higher FAPI uptake and improved lesion detection compared with [¹⁸F]FDG PET across most histological subtypes, with particularly notable advantages in low- and intermediate-grade tumors. However, FAPI uptake varies according to histological subtype. In metastatic bone disease, FAPI PET detects more lesions than [¹⁸F]FDG PET, particularly osteolytic and marrow-based metastases. The benefit is greatest in tumor entities with low [¹⁸F]FDG uptake, though at the cost of reduced specificity, as benign skeletal and fibroinflammatory processes also take up the tracer. As FAPI and [¹⁸F]FDG reflect different tumor biology with distinct strengths, their roles are increasingly regarded as complementary rather than competing. Beyond imaging, FAPI PET facilitates patient selection for FAP-targeted radioligand therapy, with early clinical experience demonstrating feasibility and encouraging preliminary evidence of disease control. Prospective studies are needed to define its clinical impact, establish standardized interpretation and response criteria, and determine the role of FAPI-based imaging and therapy in the management of musculoskeletal malignancies.